The present invention relates to the treatment of infections of hepatitis virus using lipid derivatives of antiviral nucleoside analogues. More particularly, the present invention relates to lipid, especially phospholipid, derivatives of antiviral nucleoside analogues which can be integrated into the structure of liposomes, thereby forming a more stable liposomal complex that can deliver greater amounts of antihepatitis drugs to target cells with less toxicity.
The publications and other reference materials referred to herein are hereby incorporated by reference, and are listed for convenience in the bibliography appended at the end of this specification.
Many nucleoside analogues are known to have activity against the hepatitis B virus (HBV). Recently, Lee et al.(1) as well as Kassanides et al.(2) have shown that dideoxynucleosides such as dideoxycytidine (ddC), dideoxyinosine (ddI), dideoxyadenosine (ddA), dideoxythymidine (ddT), dideoxyguanosine (ddG) and dideoxydiaminopurine are active against duck hepatitis B in vitro and in vivo (1,2). These drugs are thought to be effective because they inhibit a reverse transcriptase the hepatitis B virus utilizes at some stage of its life cycle. The triphosphates of other nucleosides such as acyclovir (ACV), bromovinyldeoxyuridine (BVdU), and deoxyfluoro-arabinosyliodocytosine (FIAC) have also been reported to inhibit the DNA polymerase of hepatitis B virus from humans and woodchucks (3). The arabinofuranosyladenines (ara-A) and arabinofuranosyl-cytidines (ara-C) inhibit the human hepatitis B DNA polymerase, and ara-A has activity when administered to individuals suffering from chronic type B hepatitis (4). Further, Matthes et al. report that 2',3'-dideoxy-3'-fluorothymidine (FddThd), 2',3'-didehydro-2',3'-dideoxythymidine (ddeThd), 3'-fluoro-5-methyl-deoxycytidine (FddMeCyt), 3'-chloro-5-methyl-deoxycytidine ((ClddMeCyt), and 3'-amino-5-methyl-deoxycytidine (AddMeCyt) almost completely block production of hepatitis B virus particles in an HBV DNA-transfected cell line in vitro (5).
The antihepatitis B nucleoside analogues described above have very short half lives when administered to humans or animals as the free compound. After 4 to 6 hours, their levels in tissue and plasma are very low or negligible. These nucleoside analogues are also toxic, and their toxicity can be a limiting factor in therapeutic regimens. Clearly, it would be useful to administer the antihepatitis B nucleosides (dideoxynucleosides, acyclic nucleosides, and deoxynucleosides) in a form which could be targeted to the liver parenchymal cells, and which could maintain higher tissue levels over longer time periods.